CN107245087B - 99mTc marks glucosan derivative and preparation method and application containing isonitrile - Google Patents
99mTc marks glucosan derivative and preparation method and application containing isonitrile Download PDFInfo
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Abstract
The invention discloses a kind of general structure be [99mTc‑(CNDG)6]+'s99mThe glucosan derivative and preparation method and application containing isonitrile of Tc label.The analog derivative with99mTc+For center core, isonitrile carbon atom in CNDG with99mTc (I) coordination formed hexa-coordinate [99mTc‑(CNDG)6]+Complex.By the synthesis of ligand CNDG and the preparation of CNDG froze-dried kit, obtain [99mTc‑(CNDG)6]+Derivative.Derivative of the invention has good stability, and preparation is easy, has higher intake and good delay in tumor locus, tumour/non-target ratio is high, is that function admirable can be used for the novel of tumor imaging99mThe glucosan derivative containing isonitrile of Tc label, it is easy to promote and utilize.
Description
Technical field
The invention belongs to radiopharmaceutical chemistries and clinical nuclear medicine technical field, and in particular to a kind of99mTc label is containing different
The glucosan derivative and preparation method and application of nitrile.
Background technique
Currently, in clinical medicine domain, malignant tumour has become the first killer for threatening human health and life, tumour
Annual morbidity is still in rising trend with the death rate, is early diagnosed to tumour, early treatment and personalized treatment are to reduce
The most effective measure of tumor mortality rate.Traditional non-wound lesion detection developing method such as X ray method, CT, MRI etc., mainly
It is the form of internal organs and construction imaging under pathological state, and nuclear medicine molecular image technology such as positron emission tomography
(PET) and single-photon emission tomography art (SPECT) can reflect from molecular level the physiology of tumour, pathology, metabolism and
The variation of function.Currently, as organically blending for the image technologies such as PET/CT, PET/MR and SPECT/CT is examined in tumour early stage
It plays an increasingly important role in terms of disconnected and personalized treatment, to adapt to nuclear medicine molecular image technology in clinical diagnosis and treatment
It is widely applied and fast-developing demand, the research for the Radiogenic neoplasm molecular probe for relying interdependent as the technology just seems outstanding
It is urgent and important.
Currently, being clinically using most tumor developers18F- fluorodeoxyglucose (18F-FDG), imaging results
Preferably, but its diagnosis expense costly limits its extensive use to a certain extent, especially in country underdeveloped
It is not yet common with area application.Due to99mTc has suitable half-life period (T1/2=6.02 h), the γ single photon emission of 140kev
The advantages that, and99Mo-99mThe popularization and application of Tc generator so that99mThe preparation of Tc radiopharmaceutical is simple, can medicine box, it is inexpensive easily
It obtains, reliable in quality, therefore develops novel with clinical value99mTc labelled glucose class tumor developer has important
Realistic meaning.Isonitrile is the organic compound that a kind of general formula is RNC, wherein nitrogen-atoms band part positive charge, carbon atom band portion
Divide negative electrical charge.Studies have shown that carbon atom in isonitrile can be with99mTc (I) coordination formed positive monovalence [99mTc-(CNR)6]+Match
Object is closed, wherein99mTc- methoxy isobutyl isonitrile (99mTc-MIBI it) is clinically had been widely used as myocardial perfusion imaging agent
And the imaging agent is found in clinic also there is certain close function of tumor.Isonitrile molecule is in tumor cells probe of the invention
?99mTc and glycan molecule connect, play bifunctional linking reagent effect, make tumoraffin function carbohydrate metabolism with99mTc tracer function
It can be integrated.Based on background above, a kind of function admirable is sought in research and development99mTc labelled glucose class tumor cells probe, will
Glucosamine is converted into the glucosan derivative (referred to as are as follows: CNDG) containing isonitrile, then utilizes the carbon atom in isonitrile ligand
With99mTc coordination, obtains stable99mGlucosan derivative of the Tc label containing isonitrile, which is used as tumor developer, important science meaning
The vital task that adopted and wide application prospect and this field faces.
Summary of the invention
The object of the present invention is to provide one kind to have good stability, and preparation is easy, for tumor developer99mTc label
Glucosan derivative containing isonitrile, while preparation method being provided.
To achieve the goals above, the invention adopts the following technical scheme: it is a kind of99mThe glucose containing isonitrile of Tc label
Derivative, general structure be [99mTc-(CNDG)6]+, structural formula is as follows:
In the structural formula: with99mTc+Core is center core, in CNDG the carbon atom of isonitrile with99mTc (I) coordination forms six and matches
Position [99mTc-(CNDG)6]+Complex, n are the integer greater than 2.
99mThe preparation method of the glucosan derivative containing isonitrile of Tc label, preparation step are as follows:
A: the synthesis of ligand CNDG:
The structural formula of compound (II) is as follows:
Appropriate glucosamine HCL is weighed in 25mL round-bottomed flask, anhydrous methanol dissolution is added, is then added appropriate
Reaction 30min is stirred at room temperature in NaOH.Reaction flask is placed in ice-water bath later, is slowly added dropwise under stirring in right amount containing compound
(II) methanol solution continues to react 3h under ice-water bath after being added dropwise, and vacuum distillation removes solvent, column layer after reaction
Analysis purifying (methylene chloride-methanol) obtains ligand CNDG:
Specific synthetic route are as follows:
b:[99mTc-(CNDG)6]+The preparation of complex:
Prepare CNDG froze-dried kit: by by CNDG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH 5
~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CNDG, SnCl2.2H2O 0.03mg
And its suitable sodium citrate, it is spare after freeze-dried；
The Na that proper amount of fresh is eluted99mTcO4It is added to CNDG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved, boiling
Heating water bath 20min can be obtained it is described [99mTc-(CNDG)6]+Complex；
Specific preparation step is as follows:
The synthesis of 1.CN2DG
Aminoglucose hydrochloride 91mg (0.423mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 17mg (0.423mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 114mg (0.466mmol) II (n=2), is continued after being added dropwise
3h is reacted under ice-water bath, vacuum distillation removal methanol solvate, residual solids cross silicagel column (methylene chloride: methanol after reaction
=5:1) it isolates and purifies, CN2DG is obtained after dry；
The synthesis of 2.CN3DG
Aminoglucose hydrochloride 117mg (0.544mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 22mg (0.544mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 156mg (0.598mmol) II (n=3), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN3DG after dry；
The synthesis of 3.CN4DG
Aminoglucose hydrochloride 129mg (0.600mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 24mg (0.600mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 182mg (0.660mmol) II (n=4), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN4DG after dry；
The synthesis of 4.CN5DG
Aminoglucose hydrochloride 147mg (0.684mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 27mg (0.684mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 217mg (0.752mmol) II (n=5), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN5DG after dry；
5.99mTc-(CN2DG)6 +、99mTc-(CN3DG)6 +、99mTc-(CN4DG)6 +With99mTc-(CN5DG)6 +Synthesis
Prepare CN2DG froze-dried kit: by by CN2DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN2DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN2DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN2DG)6]+Complex；
Prepare CN3DG froze-dried kit: by by CN3DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN3DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN3DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN3DG)6]+Complex；
Prepare CN4DG froze-dried kit: by by CN4DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN4DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN4DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN4DG)6]+Complex；
Prepare CN5DG froze-dried kit: by by CN5DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN5DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN5DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN5DG)6]+Complex.
Chemical synthesis reagent raw material of the present invention is commercial goods, from a wealth of sources.It is prepared by the above method
[99mTc-(CNDG)6]+The radiochemical purity of complex is greater than 90%, is hydroaropic substance, and vitro stability is good.It is in lotus
Tumor mouse tumor position have it is higher intake with good delay, tumour/muscle and tumour/blood ratio are good, liver, kidney,
Uptake values in the non-target organ such as lung are low, are that a kind of function admirable can be used for the novel of tumor imaging99mTc label contains isonitrile
Glucosan derivative, reached goal of the invention.
The present invention [99mTc-(CNDG)6]+Performance measurement:
1.[99mTc-(CNDG)6]+The chromatography of complex is identified
The identification of object radiochemical purity is marked using thin layer chromatography method (TLC), expansion system used is first
Alcohol/polyamide film piece, under such system, the Rf value of each radioactive component is as shown in the table.
90% is all larger than by the radiochemical purity of the measured marker of above-mentioned chromatography identification.
2. the measurement of lipid
It takes the 100 μ L of marking fluid (50 μ Ci) that normal saline dilution is crossed to be placed in the centrifuge tube of 2mL, then to centrifuge tube
In the n-octyl alcohol of 800 μ L and the PBS of 700 μ L is added, cover centrifugation pipe cap and be vortexed 3 min (2500r/min), stand to solution point
It is centrifuged 3min (3000r/min) in centrifuge after layer, 100 μ L of 3 parts of upper organic phases and lower layer's water phase is respectively taken, in γ-
The radiocounting of organic phase and water phase, lipid P=organic phase radiocounting/water are measured in counter respectively
Phase radial pattern counts, and is usually indicated using Log P as lipid.After measured99mTc-(CN2DG)6 +、99mTc-
(CN3DG)6 +、99mTc-(CN4DG)6 +With99mTc-(CN5DG)6 +Log P value be respectively -4.26 ± 0.12, -4.01 ± 0.17,
- 3.84 ± 0.06, -3.57 ± 0.35, illustrate that marker is the parent of water-soluble substances and the increase respective markers object with n value
Water reduced performance.
3. Stability Determination
Marker is placed different time (1,2,3,4 hour) at room temperature and in 37 DEG C of mice serums respectively to measure afterwards
Its radiochemical purity, the experimental results showed that each marker radiates at room temperature and after placing 4 hours in 37 DEG C of mice serums
Chemical purity is all larger than 90%, illustrates it with good vitro stability.
4. tumor-bearing mice vivo biodistribution measure of spread
Marking fluid (0.1mL, 74KBq) is injected in Mice Body by tail vein, is write down after injection time when different
The mouse neck that breaks is put to death (5 mouse of each phase) by phase (30min, 60min, 120min), takes out the heart after dissection, liver, lung, kidney,
Spleen, stomach, meat, blood, the organ of interest such as tumour measure the radiocounting of each internal organs with γ-counter respectively, and by each
The uptake values (as unit of %ID/g) of each internal organs are obtained after the mass conversion of internal organs, each marker is intracorporal in tumor-bearing mice
Bio distribution the results are shown in Table 1- table 4:
Table 1.99mTc-(CN2DG)6 +Bio distribution result (x ± s, %ID/g) in mice bearing S180
Table 2.99mTc-(CN3DG)6 +Bio distribution result (x ± s, %ID/g) in mice bearing S180
Table 3.99mTc-(CN4DG)6 +Bio distribution result (x ± s, %ID/g) in mice bearing S180
Table 4.99mTc-(CN5DG)6 +Bio distribution result (x ± s, %ID/g) in mice bearing S180
It will99mTc-(CN2DG)6 +、99mTc-(CN3DG)6 +、99mTc-(CN4DG)6 +With99mTc-(CN5DG)6 +With entered three
Phase clinical research99mTc-ECDG(David J.et al Imaging with 99mTc-ECDG Targeted at the
Multifunctional Glucose Transport System:Feasibility Study with Rodents[J]
.Radiology, 2003,226 (2): 465-473) compare in tumor-bearing mice vivo biodistribution distributed data, it the results are shown in Table 5.
Table 599mTc-(CN2DG)6 +、99mTc-(CN3DG)6 +、99mTc-(CN4DG)6 +、99mTc-(CN5DG)6 +With99mTc-
ECDG tumor-bearing mice vivo biodistribution distributed data after injecting 0.5h compares (%ID/g)
The above result shows that99mTc-(CN2DG)6 +、99mTc-(CN3DG)6 +、99mTc-(CN4DG)6 +、99mTc-(CN5DG)6 +
Intake and tumor/blood, tumour/liver ratio in tumour is superior to99mTc-ECDG, it is equal in the intake of the internal organs such as liver, kidney
It is lower than99mTc-ECDG, the novel tumor imaging agent that can be used as function admirable promote and apply.
5.SPECT imaging measurement
By what is prepared99mTc-(DG3NC)6 +Or99mTc-(DG5NC)6 +It is small that (0.2mL, 700 μ Ci) tail vein injects lotus knurl
In mouse body, 1h carries out SPECT imaging, and SPECT image results both show to all have apparent aggregation in tumor locus, while
Also have higher concentration in kidney, and absorbed in other organs it is lower, show its can become function admirable tumor developer.
Specific embodiment
The present invention is described in detail by the following examples: it is a kind of99mThe glucosan derivative containing isonitrile of Tc label, general structure
For [99mTc-(CNDG)6]+, preparation step is as follows:
A: the synthesis of ligand CNDG::
Appropriate glucosamine HCL is weighed in 25mL round-bottomed flask, anhydrous methanol dissolution is added, is then added appropriate
Reaction 30min is stirred at room temperature in NaOH.Reaction flask is placed in ice-water bath later, is slowly added dropwise under stirring in right amount containing compound
(II) methanol solution continues to react 3h under ice-water bath after being added dropwise, and vacuum distillation removes solvent, column layer after reaction
Analysis purifying (methylene chloride-methanol) obtains ligand CNDG:
Specific synthetic route are as follows:
b:[99mTc-(CNDG)6]+The preparation of complex, specific preparation process is as follows:
The synthesis of 1.CN2DG
Aminoglucose hydrochloride 91mg (0.423mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 17mg (0.423mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 114mg (0.466mmol) II (n=2), is continued after being added dropwise
3h is reacted under ice-water bath, vacuum distillation removal methanol solvate, residual solids cross silicagel column (methylene chloride: methanol after reaction
=5:1) it isolates and purifies, CN2DG product 83mg, yield 75% are obtained after dry.1H-NMR(400MHz,D2O):δ(ppm)3.65-
3.89 (m,7H),3.34-3.44(m,2H),2.65(t,2H).HRMS Calculated for,C10H16N2O6Na [M+Na]+
283.0911,found 283.0906.IR(KBr)/cm-1:3303.24(-OH),2933.85, 2149.76(-NC),
1647.28 (- C=O), 1560.48,1303.03,586.39.
The synthesis of 2.CN3DG
Aminoglucose hydrochloride 117mg (0.544mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 22mg (0.544mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 156mg (0.598mmol) II (n=3), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN3DG product 85mg, yield 57% after dry.1H-NMR(400MHz,D2O):δ(ppm)3.65-
3.85 (m,5H),3.42-3.49(m,4H),2.37-2.42(m,2H),2.19(t,2H).HRMS Calculated for
C11H18N2O6Na[M+Na]+,297.1057,found,297.1052.IR(KBr)/cm-1:3299.38(-OH), 2932.89,
2149.76 (- NC), 1647.28 (- C=O), 1558.55,1303.03,588.31.
The synthesis of 3.CN4DG
Aminoglucose hydrochloride 129mg (0.600mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 24mg (0.600mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 182mg (0.660mmol) II (n=4), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN4DG product 108mg, yield 63% after dry.1H-NMR(400MHz,D2O):δ(ppm)3.65-
3.89 (m,5H),3.38-3.44(m,4H),2.28(t,2H),1.60-1.75(m,4H).HRMS Calculated for
C12H21N2O6[M+H]+,289.1394,found 289.1396.IR(KBr)/cm-1:3295.52(-OH), 2943.50,
2150.72 (- NC), 1645.35 (- C=O), 1542.15,1093.69,1033.89,599.89.
The synthesis of 4.CN5DG
Aminoglucose hydrochloride 147mg (0.684mmol) is weighed in 25mL round-bottomed flask, 3mL anhydrous methanol is added
Then NaOH 27mg (0.684mmol) is added in dissolution, reaction 30min is stirred at room temperature.Reaction flask is placed in ice-water bath later,
It is slowly stirred down the methanol solution 1mL being added dropwise dissolved with 217mg (0.752mmol) II (n=5), is continued after being added dropwise
3h is reacted under ice-water bath, after reaction vacuum distillation fall methanol solvate, residual solids cross silicagel column (methylene chloride: methanol=
It 5:1) isolates and purifies, obtains CN5DG product 161mg, yield 78% after dry.1H-NMR(400MHz,D2O):δ(ppm)3.74-
3.82 (m,3H),3.63-3.70(m,2H),3.34-3.40(m,4H),2.24(q,2H),1.53-1.59(m,4H), 1.33-
1.38(m,2H).HRMS Calculated for C13H22N2O6Na[M+Na]+,325.1374,found 325.1370.IR
(KBr)/cm-1: 3294.56 (- OH), 2941.57,2148.79 (- NC), 1645.35 (- C=O), 1538.30,1093.69,
1032.93,590.85.
5. 99mTc-(CN2DG)6 +、99mTc-(CN3DG)6 +、99mTc-(CN4DG)6 +With99mTc-(CN5DG)6 +Synthesis
Prepare CN2DG froze-dried kit: by by CN2DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN2DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN2DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN2DG)6]+Complex.
Prepare CN3DG froze-dried kit: by by CN3DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN3DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN3DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN3DG)6]+Complex.
Prepare CN4DG froze-dried kit: by by CN4DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN4DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN4DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN4DG)6]+Complex.
Prepare CN5DG froze-dried kit: by by CN5DG, SnCl2.2H2O, sodium citrate etc. is dissolved in appropriate secondary water, pH
5~6, it is sub-packed in after completely dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CN5DG, SnCl2.2H2O
0.03mg and its suitable sodium citrate, it is spare after freeze-dried.
By the Na of the fresh elution of 1-5mL99mTcO4It is added to CN5DG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved,
Boiling water bath heating 20min can be obtained it is described [99mTc-(CN5DG)6]+Complex.
It is described above99mThe glucosan derivative containing isonitrile of Tc label answering in the field of nuclear medicine as tumor developer
With.
It is served only for illustrating the present invention described in above-described embodiment, but is not intended to limit the scope of the invention.
Claims (3)
1. a kind of99mTc label the glucosan derivative containing isonitrile, general structure be [99mTc-(CNDG)6]+, structural formula is such as
Under:
In the structural formula: with99mTc+Core is center core, in CNDG the carbon atom of isonitrile with99mTc (I) coordination forms hexa-coordinate
[99mTc-(CNDG)6]+Complex, n are the integer greater than 2.
2. as described in claim 199mThe preparation method of the glucosan derivative containing isonitrile of Tc label, preparation step are as follows:
A: the synthesis of ligand CNDG:
The structural formula of compound (II) is as follows:
Appropriate glucosamine HCL is weighed in 25mL round-bottomed flask, anhydrous methanol dissolution is added, appropriate NaOH is then added,
Reaction 30min is stirred at room temperature；Reaction flask is placed in ice-water bath later, the appropriate first for containing compound (II) is slowly added dropwise under stirring
Alcoholic solution continues to react 3h under ice-water bath after being added dropwise, after reaction vacuum distillation removing solvent, column chromatographic purifying,
Obtain ligand CNDG:
Specific synthetic route are as follows:
b:[99mTc-(CNDG)6]+The preparation of complex:
Prepare CNDG froze-dried kit: by by CNDG, SnCl2.2H2O, sodium citrate is dissolved in appropriate secondary water, and pH 5-6 fills
It is sub-packed in after dividing dissolution with 1mL in clean penicillin bottle, every bottle of 1.0mg containing CNDG, SnCl2.2H2O 0.03mg and its suitable
The sodium citrate of amount, it is spare after freeze-dried；
The Na that proper amount of fresh is eluted99mTcO4It is added to CNDG froze-dried kit, is sufficiently shaken up, after solid is completely dissolved, boiling water bath
Heating 20min can be obtained it is described [99mTc-(CNDG)6]+Complex.
3. as described in claim 199mThe glucosan derivative containing isonitrile of Tc label is aobvious in nuclear medicine image field preparation tumour
As the application in agent.
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| CN201710451094.8A CN107245087B (en) | 2017-06-15 | 2017-06-15 | 99mTc marks glucosan derivative and preparation method and application containing isonitrile |
| US16/310,909 US11628228B2 (en) | 2017-06-15 | 2018-01-24 | 99mTc-labeled isonitrile-containing glucose derivative and preparation method and use thereof |
| JP2019565601A JP6770207B2 (en) | 2017-06-15 | 2018-01-24 | 99mTc-labeled isocyanide-containing glucose derivative and its preparation method and application |
| CA3056024A CA3056024C (en) | 2017-06-15 | 2018-01-24 | 99mtc-labelled isonitrile-containing glucose derivative and preparation method and use thereof |
| KR1020197028088A KR102392319B1 (en) | 2017-06-15 | 2018-01-24 | 99m-Tc-labeled isonitrile-containing glucose derivative and method and use thereof |
| DE112018003015.6T DE112018003015B4 (en) | 2017-06-15 | 2018-01-24 | 99mTc-LABELED ISONITRILE-CONTAINING GLUCOSE DERIVATIVE AND METHOD OF MANUFACTURE AND USE THEREOF |
| GB1907083.8A GB2570609B (en) | 2017-06-15 | 2018-01-24 | 99mTc-labeled isonitrile-containing glucose derivative and preparation method and use thereof |
| PCT/CN2018/073950 WO2018227977A1 (en) | 2017-06-15 | 2018-01-24 | 99mtc-labelled isonitrile-containing glucose derivative and preparation method and use |
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| CN109320557B (en) * | 2018-10-26 | 2020-10-02 | 北京师范大学 | 99mTc(CO)3Nuclear-labeled isonitrile-containing palbociclib derivative and preparation method and application thereof |
| CN111138504B (en) * | 2020-01-13 | 2021-03-30 | 北京师范大学 | A kind of99mTc-CNPEDG complex and preparation method and application thereof |
| CN111518137B (en) * | 2020-05-09 | 2021-05-14 | 北京师范大学 | Technetium-99 m marked isonitrile-containing amino acid derivative and preparation method and application thereof |
| CN112175025B (en) | 2020-10-13 | 2021-12-21 | 北京师范大学 | Glucose derivative containing benzene ring and application thereof |
| CN113150032B (en) * | 2021-04-27 | 2022-09-16 | 北京师范大学 | Technetium-99 m labeled isonitrile-containing folic acid derivative and preparation method and application thereof |
| CN113583066B (en) * | 2021-07-23 | 2023-03-14 | 北京师范大学 | Mannose derivative and application thereof |
| CN114225057B (en) * | 2021-12-22 | 2023-03-24 | 北京师范大学 | Technetium-99 m labeled isonitrile-containing UBI 29-41 derivative and preparation method and application thereof |
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| US4735793A (en) * | 1985-08-30 | 1988-04-05 | Massachusetts Institute Of Technology | Carboxy, carboalkoxy and carbamile substituted isonitrile radionuclide complexes |
| CN102146098A (en) * | 2011-03-02 | 2011-08-10 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
| CN102993243A (en) * | 2012-12-19 | 2013-03-27 | 北京师范大学 | 99mTc marked glucose derivative and preparation method and application thereof |
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| CN1283647C (en) | 2002-11-29 | 2006-11-08 | 北京师范大学 | Technetium-99m marked isonitrile group mating material, preparing process and uses thereof |
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| US4735793A (en) * | 1985-08-30 | 1988-04-05 | Massachusetts Institute Of Technology | Carboxy, carboalkoxy and carbamile substituted isonitrile radionuclide complexes |
| CN102146098A (en) * | 2011-03-02 | 2011-08-10 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
| CN102993243A (en) * | 2012-12-19 | 2013-03-27 | 北京师范大学 | 99mTc marked glucose derivative and preparation method and application thereof |
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| GB2570609A (en) | 2019-07-31 |
| JP6770207B2 (en) | 2020-10-14 |
| GB2570609B (en) | 2022-08-17 |
| KR20190121824A (en) | 2019-10-28 |
| GB201907083D0 (en) | 2019-07-03 |
| CN107245087A (en) | 2017-10-13 |
| US11628228B2 (en) | 2023-04-18 |
| US20210220492A1 (en) | 2021-07-22 |
| DE112018003015T5 (en) | 2020-03-05 |
| WO2018227977A1 (en) | 2018-12-20 |
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| KR102392319B1 (en) | 2022-04-29 |
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